The main goal of this proposal is to elucidate how demography and natural selection have shaped the organization of sequence variation and linkage disequilibrium (LD) in the human genome and across human populations. Such an understanding will provide critical background information needed to design studies aimed at dissecting the genetic bases of complex phenotypes. To advance these goals, the investigators propose the following specific aims: 1. To survey sequence variation and LD in three ethnically diverse populations at up to ten pairs of tightly, but not completely linked loci to: a) evaluate the effect of different demographic scenarios on patterns of variation and LD; b) estimate the parameters of the inferred demographic model for human populations; and c) develop expectations for the amount and inter-locus variability of sequence variation and LD at the genome-wide level by computer simulations. For each locus 1-2 kb of sequence will be surveyed for variation in samples of 30-50 chromosomes from three large populations representative of the major ethnic groups: Cameroon (Africa), Han Chinese (Asia) and Italians (Europe). The investigators have already shown by computer simulations that this is a highly efficient and informative approach to develop expectations for the pattern of variation and LD at the genome-wide level. In addition they will be able to characterize how genetic variation and LD is organized across major ethnic groups. 2. The investigators will survey sequence variation and reconstruct haplotypes around two common variants: G6PDdef and Duffy O blood group (FY). These are known to have evolved under positive selection in African populations. In particular, they will estimate nucleotide diversity and LD in the regions flanking the site under selection and compare these quantities in neutrally evolving regions. This analysis is aimed at characterizing the signature of selection on the pattern of LD and sequence variation linked to the variants examined.